Fungal diseases are a major clinical problem in current medical practice. A major unsolved problem in the field of medical mycology is the relationship between host genetics and host susceptibility. Although there is circumstantial evidence that susceptibility to fungal diseases is determined by host genetic factors, this area is relatively unexplored. Current technologies for identifying resistance and susceptibility genes in mammals are cumbersome, slow, and inefficient and, new approaches are urgently needed. For human mycoses the difficulties in using standard genetic approaches are compounded by the fact that many types of fungal diseases occur at relatively low frequency in human populations. Our laboratory has recently established that the interactions of the human pathogenic fungus Cryptococcus neoformans with the ameboid predators Acanthamoeba castellani and Dictostylium discoideum are very similar to that observed with mammalian macrophages. Our group has shown that C. neoformans can infect D. discoideum, replicate intracellularly, and kill the amoeboid cells. D. discoideum is a slime mold, which has proven to be an extremely useful system for the studying such cellular processes as chemotaxis and cell-to-cell signaling. The fact that D. discoideum can be host for C. neoformans provides the opportunity to use this genetically malleable ameboid host to dissect host-pathogen interactions in a simple eukaryote. This application proposes to exploit this system to identify D. discoideum susceptibility and resistance genes that can lead to the identification of homologous mammalian genes in macrophages. We anticipate that the novelty of this approach combined with the experimental versatility of the D. discoideum system will lead to the identification of genetic pathways that are not immediately obvious from standard fungal-macrophage experiments.